Acquired bone marrow failure syndromes, such as myelodysplastic syndrome (MDS), are frequently caused by genetic mutations. Both the underlying mechanism and prognosis of MDS have been attributed to specific driver gene mutations, and genetic classification systems have led to improved clinical outcomes. Bone marrow failure, and MDS have been linked to autoimmune diseases although the clinical relevance of these associations has not been well defined. We identified an acquired mutation in the gene UBA1 that occurs in the earliest progenitors in the bone marrow, and leads to common inflammatory rheumatic and hematologic diseases such as rheumatoid arthritis and myelodysplastic syndrome. Patients with mutations in UBA1 have VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, with increased mortality from a variety of severe inflammatory and hematologic clinical signs, marked in large part by bone marrow failure that occurs late in life. Identification of UBA1 mutations as disease causing is paradigm shifting because it demonstrates the contribution of acquired mutations in common rheumatic diseases, highlights the role of ubiquitylation in inflammation, and reveals the importance of molecular diagnoses to improve clinical care in diseases with overlapping rheumatologic and bone marrow failure symptoms. Here we intend to expand upon these findings and identify and molecularly characterize additional novel, somatic, genetic drivers of acquired bone marrow syndromes, particularly involving overlapping autoimmune manifestations. We have already identified and sequenced a large number of patients with acquired bone marrow failure syndromes using exome and genome sequencing and have identified novel candidate driver mutations in UBA1. We propose here to expand upon these findings beyond UBA1 and perform more in-depth genetic analysis using long read genome sequencing to try to identify structural and non-coding variants that may contribute to VEXAS like phenotype. We will cross reference this data with our deep exome sequencing to both determine the sensitivity of the approach and confirm findings. Finally, we propose to molecularly characterize novel variants identified in UBA1 and those identified through long read sequencing to determine if these mutations are pathogenic. Together, our work will determine new genetic causes of acquired bone marrow failure missed on previous sequencing efforts, while better defining the cellular and molecular mechanisms underlying these diseases (what, where, and when). As a physician scientist, my overarching goal is to use these insights to improve care for patients with unexplained hematologic and inflammatory symptoms. Genetic reclassification, as has already been shown for VEXAS/UBA1 in a short period of time, will lead to improved prognosis and targeted care for patients going forward.
